The myelodysplastic syndromes (MDS) represent a group of perplexing, heterogeneous, hematological disorders characterized by the clinical paradox of variable cytopenias despite generally cellular bone marrows in the setting of monoclonal hemopoiesis. (Resegotti L. 1993. Haematologica 25(3):191–204; Yoshida Y. et al. 1993. Int J Hematol 57:87–97.) There are two types of MDS, one for which no cause is known called primary MDS, and the other which follows known and documented exposure to toxic/chemical agents such as chemotherapy or radiation, called secondary MDS. The vast majority of patients constituting approximately 90% in all, belong to the primary MDS category, while in 10% cases, the disease is a result of damage to the marrow produced by chemicals such as chemotherapy for a prior malignancy or exposure to radiation. The incidence of MDS clearly increases with age as well as following exposure to known marrow toxins. (Aul C., et al. 1992. Br J Haematol 82:358–67.) Frequently encountered with the incidence of MDS are progressively mutated clones reflecting a stepwise accumulation of genetic damage (Jacobs A. 1987. Br J Cancer Review 55:1–5), as well as confounding immunological defects represented by the detection of circulating immune complexes, lowered T-cell counts and accompanying immune disorders. (Colombat P. H., et al. 1988. Cancer 61:1075–81.) MDS sporadically has been found to co-exist with or follows a diagnosis of multiple myeloma (Mufti G. J., et al. 1983. Br J Haematol 54:91–6) or Fanconi's anemia (Auerback A. D. and Allen R. G. 1991. Cancer Genet Cytogenet 15:1–12).
MDS patients present with a lowering of one or more type of these blood cells (WBCs, RBCs, or platelets), the most common cell type affected being red cells, so that anemia is the universal hallmark of this disease. It is referred to as a “refractory” anemia because the anemia of MDS patients is “refractory” to or does not respond to the commonly used therapies for anemia such as iron, and/or vitamins. Lowering of the blood cells is known as “cytopenia,” and therefore MDS patients may suffer from monocytopenia (lowering of only one cell-type), or bi-cytopenia (two cell-types), or tri-cytopenia (three cell-types). Patients with MDS present with one or more of the following abnormalities in the blood: anemia or RBC count; leukopenia or low WBC count, and thrombocytopenia or low platelet count.
All patients with MDS show “dysplastic” or abnormal looking cells in their marrows, however they are in all stages of maturation. In a normal marrow, the immature cells or “blasts” constitute less than 5% of the total population, and in approximately two-thirds of MDS patients as well, the blasts continue to be at this low level. In addition, red cell precursors in the blood can show iron deposits in the form of a ring around the nucleus of the cell, and such cells are called “ringed sideroblasts.” A third of MDS cases however, present with more than 5% blasts in the marrow, and they are said to have “excess blasts.” This excess in blasts can range from 6% to 29%, and the patient is still classified as having MDS, but if this count reaches 30%, then the disease is no longer MDS, but is said to have “transformed into acute leukemia.”
Oftentimes MDS eventually transform into acute myeloid leukemia (AML). Incidence of transformation to AML appears to be highly correlated with the percentage of blasts in the bone marrow (BM) at presentation (Sanz G. F., et al. 1989. Blood 74:395–408), as well as certain complex cytogenetic abnormalities (Morel P., et al. 1993. Leukemia 7:1315–21). However, not infrequently, refractory anemia (RA) patients have been noted to progress directly to AML without an orderly, expected progression through RA to RA with excess blasts (RAEB) to AML. (Layton D. M. and Mufti G. J. 1986. Blut 53:423–36.)
While the disease presents with low blood counts, the real abnormality lies in the organ which is responsible for producing these abnormal or “dysplastic” cells, that is the bone marrow. The bone marrow contains a large quantity of stem cells, so called because they give birth to the blood cells. MDS is a disease in which something has gone wrong with one of the stem cells, making it dysplastic, so that all its daughters are similarly affected and look dysplastic. The affected stem cell can divide faster than its normal counterparts, and therefore rapidly fills up the compartment in the bone marrow which is responsible for producing cells that eventually come out in the blood. With time, all the cells in the blood, and almost 99% of cells in the marrow of MDS patients are descended from the transformed, abnormal parent.
Conventionally, MDS have been considered to be slowly proliferative disorders. Perhaps the most unexpected initial observation in this context emerged following studies related to the proliferative activity of hematopoietic cells in MDS bone marrows. In vivo measurement of the cell-birth rate in the bone marrow aspirate and biopsies of these patients following infusions of thymidine analogues iodo- and/or bromodeoxyuridine (IudR/BrdU) showed that contrary to expectation, the bone marrows are not only filled with large numbers of S-phase cells (median labeling index=30%), but that the doubling time of myeloblast was found to be almost twice as rapid (33 versus 56 h) as that for AML. (Raza A., et al. 1997. Exp Hematol 25:530–5.) It was this observation of intensive proliferative activity in the marrows of MDS patients that led to the hypothesis that persistent cytopenias in this setting could be the results of either excessive intramedullary premature apoptosis of hemotopoietic cells or abnormally prolonged retention of parenchyma cells in the marrow. Yoshida had hypothesized that ineffective hematopoiesis in MDS could be due to excessive apoptosis (Yoshida Y. 1993. Leukemia 7(1):144–6). Clark and Lampert actually provided morphological evidence of increased apoptotic bodies in MDS patients (Clark D. M. and Lampert I. A. 1990. Leuk Lymphoma 2:415–8). Several techniques to quantify the incidence of apoptosis accurately in MDS marrows were employed, including: in situ end labeling (ISEL), terminal deoxynucleotidyl transferase-mediated UTP nick end labeling (TUNEL), flow cytometric assays and the detection of low- and high-molecular weight ‘DNA ladders’ by gel and pulsed field electrophoresis, respectively. (Raza A., et al. 1995. Am J Hematol 48:143–54; Raza A., et al. 1995. Blood 86(1):268–76; Raza A., et al. 1996. Int J Oncol 8:1257–64; Alvi S., et al. 1996. Proc Am Assoc Cancer Res (Abstr # 185) 37:27.) Results obtained uniformly supported the hypothesis. Not only were parenchyma cells belonging to all three lineages apoptotic in MDS patients, but large numbers of cells actively engaged in DNA synthesis were also found to be simultaneously undergoing programmed cell death reflecting ‘signal antonymy.’ (Mundle S., et al. 1994. J Histochem Cytochem 42(12):1533–7.) Therefore, in summary, while the marrows of MDS patients are choking with proliferating cells, these cells are frequently in the process of concomitantly committing suicide, thus accounting for the paradox of cytopenia despite hypercellular marrows.
It appears that the excessive death of cells in the bone marrow is being mediated by certain proteins called “cytokines” which are normally produced during inflammatory responses, but which are present in higher than normal concentrations in MDS marrows. The most important of these cytokines is called Tumor Necrosis Factor or TNF. In other words, high TNF levels in the marrows induces a suicidal program in cells so that instead of being released into the blood, these cells die in the marrows. Thus, even though the bone marrow is working overtime to produce more and more blood cells, they are “ineffective” since they begin to die prematurely.
Due to the complexity of MDS, no single therapeutic approach appears to have made a significant impact on survival of patients with MDS. (Cazzola M., et al. 1998. Haematologica 83:910–935; Santini V. and Ferrini P. R. 1998. Br J Haematol 102:1124–1138.) Allogeneic bone marrow (BM) transplantation, a choice available to few patients given that the median age at diagnosis is approximately 70 years, has been the only curative therapy available. (Ratanatharathom V. et al. 1993. Blood 81:2194–2199; Anderson J. E., et al. 1996. Blood 87:51–58.) Other options have ranged from supportive care to the use of stem cell transplantation. Based on the assumption that the cytopenias may reflect a primary bone marrow failure, colony-stimulating growth factors with overlapping activities designed to stimulate proliferation of hematopoietic progenitors have been extensively investigated. (Vadhan-Raj S., et al. 1987. N Engl J Med 317:1545–1552; Negrin R. S., et al. 1990. Blood 76: 36–43; Greenberg P., et al. 1993. Blood 82(suppl 1): 196a.) The problem is that administered as single agents, granulocyte-macrophage colony-stimulating factor (GM-CSF) or G-CSF rarely improves the anemia and the thrombocytopenia so commonly the pathognomonic features of MDS. Erythropoietin alone produces an improvement in the anemia of approximately 20% of patients, which increases to almost 50% when combined with G-CSF. (Hellstrom-Lindberg E. 1995. Br J Haematol 89:67–71; Hellstrom-Lindberg E., et al. 1998. Blood 92:68–75.) However, only a proportion of patients respond, the response is usually temporary, and there is some concern related to an incidence of accelerated transformation. (Hermann F., et al. 1989. Leukemia 3:335–338.)
Acute leukemia-like intensive induction therapies have been attempted in patients with high-risk MDS (those with excess blasts or chronic myelomonocytic leukemia), with as many as half the patients achieving complete remission. (Cheson B. D. 1998. Leuk Res 22:17–21; Hiddemann W., et al. 1998. Leuk Res 22:23–26.) Short duration of remission marked by a relentless return of MDS cells in most patients, treatment-related complications or mortality, frequent encounters with drug-resistant clones, and the morbidity caused by the appearance of unexpected and unusual opportunistic infections reflecting the enormously compromised state of the immune system in these patients make the intensive chemotherapy option less desirable. In summary, save for allogeneic transplantation, MDS is a universally fatal illness, and no single approach has either altered the natural history of the disease or improved survival.
Given the biologic complexity and the unpredictable course of the disease ranging from chronic, insidious, and slowly progressive cytopenia to a rapidly evolving, lethal transformation to acute leukemia, it is not surprising that therapeutic options range widely between supportive care to intensive induction-type chemotherapy. Clearly, a better understanding of the basis for cytopenias in MDS is critical to design therapies tailored for individual needs.